ABSTRACT The sympathetic nervous system innervates a number of targets, including the heart, and sympathetic activity is a critical regulator of cardiac function. Sympathetic neurons form noradrenergic synapses onto heart cells resulting in excitation of myocyte function. Interestingly, these neurons also form cholinergic synapses onto themselves and are capable of releasing acetylcholine at neuron-myocyte synapses. The cholinergic and noradrenergic properties of these neurons are regulated by two neurotrophins, NGF and BDNF. NGF promotes noradrenergic transmission via activation of Trk receptors. In contrast, BDNF acts through the p75 receptor to increase activity-dependent ACh release. While extensive work has been done defining the co-transmission properties of sympathetic neurons, little is known about how co-transmission properties are established and maintained, how the release of multiple transmitters is regulated, or the physiological relevance of local and global regulation of sympathetic properties by neurotrophins. We will use electrophysiological and imaging approaches to examine the idea that the neurotransmitter properties of sympathetic neurons are locally regulated by the expression of neurotrophins at different targets and that individual neurons can maintain multiple release profiles at different synaptic sites. We will determine the pre- and postsynaptic actions of neurotrophins at neuronal and cardiac targets. We will investigate the receptors and mechanisms that underlie synaptic modulation by neurotrophins, and will examine the relationship between neurotrophin signaling and sympathetic function in vivo. These studies will define neurotrophic mechanisms that regulate neural control of cardiovascular function.